Process for preparation of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives

ABSTRACT

The present invention provides a method of industrially advantageously producing 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives under mild conditions in a high yield. The present invention relates to a production method of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of the formula (III) or the formula (IV), which comprises reacting an α,β-unsaturated carboxylic acid of the formula (I) with a furan derivative of the formula (II) in the presence of a Lewis acid:  
                 
 
     wherein each symbol is as defined in the specification.

TECHNICAL FIELD

[0001] The present invention relates to a production method of7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives. An endoform of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivativeobtained by the method of the present invention is useful as a startingmaterial for the synthesis of medicine, agricultural chemical and thelike. For example, an endo form of7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid is a useful compound asa synthetic intermediate for Cyclophellitol, an anti-HIV drug [seeTetrahedron Letters, vol. 37, p. 3043 (1996)], as a syntheticintermediate for Validamycin A, an antibiotic [see CarbohydrateResearch, vol. 58, p. 240 (1977)], and as a synthetic intermediate forGS4104, an anti-influenza drug [see Journal of the American ChemicalSociety (J. Am. Chem. Soc.), vol. 119, p. 681 (1997); The Journal ofOrganic Chemistry (J. Org. Chem.), vol. 63, p. 4545 (1998);specification of WO 01/47906].

BACKGROUND ART

[0002] A number of physiologically active substances derived from anoxanorbornene skeleton have been found in recent years. Known productionmethods of 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivativeuseful as a synthetic intermediate for these compounds include (1) amethod comprising a reaction of acrylic acid with furan in the presenceof hydroquinone [see Carbohydrate Research, vol. 58, p. 240 (1977)], (2)a method comprising a reaction of an acrylic acid derivative with furanin the presence of tetrakis(acetonitrile)copper(I) tetrafluoroborate andhydroquinone [see The Journal of Organic Chemistry (J. Org. Chem.), vol.48, p. 1105 (1983)], (3) a method comprising a reaction of an acrylicacid derivative with furan under high pressure conditions of 1 to 2 MPa(10 to 20 kbar) [see The Bulletin of the Chemical Society of Japan(Bull. Chem. Soc. Japan), vol. 55, p. 4969 (1982)], (4) a methodcomprising a reaction of an acrylic acid ester with furan in thepresence of zinc chloride, zinc iodide or titanium chloride [see Journalof Molecular Catalysis A: Chemical (J. Mol. Catal. A: Chem.), vol. 123,p. 43 (1997)], and then hydrolysis of the ester moiety of the obtainedcompound [see Journal of Heterocyclic Chemistry (J. Heterocycl. Chem.),vol. 9, p. 561 (1972)] and the like.

[0003] The reaction to form the 7-oxabicyclo[2.2.1]hept-5-ene skeletonby Diels-Alder reaction of dienophile such as an acrylic acid derivativewith furan has been considered to resist promotion of the reaction byheating, because cycloaddition products are unstable to heat. In theabove-mentioned methods (1) and (2), therefore, the reaction is carriedout for a long time in the presence of hydroquinone as a polymerizationinhibitor, and in the above-mentioned method (3), the reaction iscarried out under high pressure conditions.

[0004] However, the method of the above-mentioned (1) is problematic inthat the reaction time is extremely long (75 days) and the yield is aslow as 33%. In addition, the method of the above-mentioned (2) is alsoproblematic in that the reaction time is long (9 days) and the yield isas low as 48%, and the method of the above-mentioned (3) essentiallyrequires a pressure reactor, which increases costs of facilities.Furthermore, the method of the above-mentioned (4) requires aDiels-Alder reaction step of an acrylic acid ester with furan and ahydrolysis step of the ester moiety, thus problematically having manysteps. Therefore, it is difficult to say that these methods areindustrially advantageous production methods of7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives.

DISCLOSURE OF THE INVENTION

[0005] It is therefore an object of the present invention to provide aproduction method capable of industrially advantageously producing a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative under mildconditions in a high yield. In other words, in the method of producing a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative directly froman acrylic acid derivative and a furan derivative, the present inventionaims at providing a method for producing the objective compound in ashorter reaction time in a high yield under mild conditions (without theneed for heating at a high temperature or pressurizing).

[0006] The present invention provides a production method of a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of theformula (III)

[0007] wherein

[0008] R¹, R² and R³

[0009] are each independently a hydrogen atom, a halogen atom, a formylgroup, a cyano group, a carboxyl group, an alkoxycarbonyl group, an acylgroup, an acyloxy group, an organic sulfinyl group, an organic sulfonylgroup or an alkyl group optionally having substituents, or R¹ and R² mayform a ring together with the carbon atoms they are bonded to, and

[0010] R⁴, R⁵, R⁶ and R⁷

[0011] are independently a hydrogen atom, an alkoxyl group, an alkylthiogroup or an alkyl group optionally having substituents, or R⁴ and R⁵,and R⁵ and R⁶ may form a ring together with the carbon atoms they arebonded to, or the formula (IV)

[0012] wherein R¹, R² R³, R⁴ R⁵ R⁶ and R⁷ are as defined above[hereinafter to be abbreviated as7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (III) and7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV),respectively], which comprises:

[0013] reacting an α,β-unsaturated carboxylic acid of the formula (I)

[0014] wherein R¹, R² and R³ are as defined above [hereinafter to beabbreviated as α,β-unsaturated carboxylic acid (I)], with a furanderivative of the formula (II)

[0015] wherein R⁴, R⁵, R⁶ and R⁷ are as defined above [hereinafter to beabbreviated as furan derivative (II)], in the presence of a Lewis acid.

[0016] The present invention provides a production method of a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of theformula (III-1)

[0017] wherein

[0018] R¹¹, R²¹ and R³¹

[0019] are each independently a hydrogen atom, a halogen atom or acarboxyl group, or R¹¹ and R²¹ may form a ring together with the carbonatoms they are bonded to, and

[0020] R⁴¹, R⁵¹, R⁶¹ and R⁷¹

[0021] are each independently a hydrogen atom or an alkyl groupoptionally having substituents, or R⁴¹ and R⁵¹, and R⁵¹ and R⁶¹ may forma ring together with the carbon atoms they are bonded to, or the formula(IV-1)

[0022] wherein R¹¹, R²¹, R³¹, R⁴¹, R⁵¹, R⁶¹ and R⁷¹ are as defined above[hereinafter to be abbreviated as7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (III-1) and7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV-1),respectively], which comprises:

[0023] reacting an α,β-unsaturated carboxylic acid of the formula (I-1)

[0024] wherein R¹¹, R²¹ and R³¹ are as defined above [hereinafter to beabbreviated as α,β-unsaturated carboxylic acid (I-1)], with a furanderivative of the formula (II-1)

[0025] wherein R⁴¹, R⁵¹, R⁶¹ and R⁷¹ are as defined above [hereinafterto be abbreviated as furan derivative (II-1)], in the presence of aLewis acid.

[0026] In a preferable embodiment, a boron compound having Lewis acidityis used as a Lewis acid. In a preferable embodiment, a Lewis acidselected from the group consisting of a borane-tetrahydrofuran complex,a borane-dimethyl sulfide complex, a boron trifluoride-diethyl ethercomplex, triacetoxyborane and tripropionyloxyborane can be also used asa Lewis acid. Alternatively, in another embodiment, a Lewis acidselected from the group consisting of anhydrous aluminum chloride,anhydrous ferric chloride and zinc chloride can be used as a Lewis acid.

[0027] The halogen atom represented by R¹, R², R³, R¹¹, R²¹ and R³¹ inthe above-mentioned formulas is exemplified by a fluorine atom, achlorine atom, a bromine atom, an iodine atom and the like.

[0028] The alkyl group represented by R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁴¹,R⁵¹, R⁶¹ and R⁷¹ is exemplified by a straight chain or branched chainalkyl group preferably having 1 to 10 carbon atoms, more preferably 1 to6 carbon atoms, such as a methyl group, an ethyl group, a propyl group,an isopropyl group, a butyl group, an isobutyl group, a tert-butyl groupand a hexyl group. These alkyl groups may have substituents and examplesof the substituent include a halogen atom such as a fluorine atom, achlorine atom, a bromine atom and an iodine atom; an alkoxyl grouppreferably having 1 to 6 carbon atoms such as a methoxy group, an ethoxygroup, a propoxy group and a butoxy group; a tri-substituted silyloxygroup such as a tert-butyldimethylsilyloxy group and atert-butyldiphenylsilyloxy group; and the like. As used herein, thetri-substituted silyloxy group means a silyloxy group substituted by 3substituents selected from an alkyl group (preferably an alkyl grouphaving 1 to 6 carbon atoms) and a phenyl group.

[0029] The alkoxyl group represented by R⁴, R⁵, R⁶ and R⁷ is exemplifiedby a straight chain or branched chain alkoxyl group preferably having 1to 10 carbon atoms, more preferably 1 to 6 carbon atoms, such as amethoxy group, an ethoxy group, a propoxy group and a butoxy group. Thealkylthio group represented by R⁴, R⁵, R⁶ and R⁷ is exemplified by astraight chain or branched chain alkylthio group preferably having 1 to10 carbon atoms, more preferably 1 to 6 carbon atoms, such as amethylthio group, an ethylthio group, a propylthio group and a butylthiogroup.

[0030] The alkoxycarbonyl group represented by R¹, R² and R³ isexemplified by an alkoxycarbonyl group wherein the alkoxyl moietypreferably has 1 to 10 carbon atoms, more preferably 1 to 6 carbonatoms, such as a methoxycarbonyl group, an ethoxycarbonyl group and atert-butoxycarbonyl group. The acyl group represented by R¹, R² and R³is exemplified by an alkanoyl group preferably having 2 to 10 carbonatoms, more preferably 2 to 6 carbon atoms, such as an acetyl group, apropanoyl group, a butanoyl group and a pivaloyl group; and an aroylgroup such as a benzoyl group. The acyloxy group represented by R¹, R²and R³ is exemplified by an alkanoyloxy group preferably having 2 to 10carbon atoms, more preferably 2 to 6 carbon atoms, such as an acetoxygroup, a propanoyloxy group, a butanoyloxy group and a pivaloyloxygroup; and an aroyloxy group such as a benzoyloxy group.

[0031] The organic sulfinyl group represented by R¹, R² and R³ is asulfinyl group to which an organic group is bonded, and examples thereofinclude an alkyl sulfinyl group optionally having substituents, anarylsulfinyl group optionally having substituents and the like. Thealkyl moiety of the alkyl sulfinyl group is an alkyl group preferablyhaving 1 to 6 carbon atoms. The aryl moiety of the arylsulfinyl group isexemplified by a phenyl group. The substituent that the alkyl sulfinylgroup may have is exemplified by an alkoxyl group (preferably an alkoxylgroup having 1 to 6 carbon atoms), a halogen atom, a cyano group, anitro group and the like. The substituent that the arylsulfinyl groupmay have on the aromatic ring is exemplified by an alkyl group(preferably an alkyl group having 1 to 6 carbon atoms), an alkoxyl group(preferably an alkoxyl group having 1 to 6 carbon atoms), a halogenatom, a cyano group, a nitro group and the like. The organic sulfinylgroup represented by R¹, R² and R³ is exemplified by a methanesulfinylgroup, an ethanesulfinyl group, a benzenesulfinyl group, ap-toluenesulfinyl group and the like.

[0032] The organic sulfonyl group represented by R¹, R² and R³ is asulfonyl group to which an organic group is bonded, and examples thereofinclude an alkylsulfonyl group optionally having substituents, anarylsulfonyl group optionally having substituents, a halosulfonyl group,an alkoxysulfonyl group optionally having substituents and the like. Thealkyl moiety of the alkylsulfonyl group is an alkyl group preferablyhaving 1 to 6 carbon atoms, and the alkoxyl moiety of the alkoxysulfonylgroup is an alkoxyl group preferably having 1 to 6 carbon atoms. Thearyl moiety of the arylsulfonyl group is exemplified by a phenyl group.The substituent that the alkylsulfonyl group and the alkoxysulfonylgroup may have is exemplified by an alkoxyl group (preferably an alkoxylgroup having 1 to 6 carbon atoms), a halogen atom, a cyano group, anitro group and the like. The substituent that the arylsulfonyl groupmay have on the aromatic ring is exemplified by an alkyl group(preferably an alkyl group having 1 to 6 carbon atoms), an alkoxyl group(preferably an alkoxyl group having 1 to 6 carbon atoms), a halogenatom, a cyano group, a nitro group and the like. The halogen atom thatthe halosulfonyl group has is exemplified by a chlorine atom, a bromineatom and the like. The organic sulfonyl group represented by R¹, R² andR³ is exemplified by a methanesulfonyl group, an ethanesulfonyl group, abenzenesulfonyl group, a p-toluenesulfonyl group, a chlorosulfonylgroup, a bromosulfonyl group, a methoxysulfonyl group, an ethoxysulfonylgroup, a trifluoromethoxysulfonyl group and the like.

[0033] The ring that may be formed by R¹ and R², R⁴ and R⁵, R¹¹ and R²¹or R⁴¹ and R⁵¹ together with the carbon atoms they are bonded to ispreferably a 4 to 7-membered ring. In the case of the formula (I), (II),(I-1) or (II-1), a cyclobutene ring, a cyclopentene ring, a cyclohexenering, a cycloheptene ring and the like are exemplified; and in the caseof the formula (III), (IV), (III-1) or (IV-1), a cyclobutane ring, acyclopentane ring, a cyclohexane ring, a cycloheptane ring and the likeare exemplified. The ring that may be formed by R⁵ and R⁶ or R⁵¹ and R⁶¹together with the carbon atoms they are bonded to is preferably a 4 to7-membered ring. In the case of the formula (II) or (II-1), acyclobutane ring, a cyclopentane ring, a cyclohexane ring, acycloheptane ring and the like are exemplified; and in the case of theformula (III), (IV), (III-1) or (IV-1), a cyclobutene ring, acyclopentene ring, a cyclohexene ring, a cycloheptene ring and the likeare exemplified. These rings may have substituents and examples of thesubstituent include an alkyl group (preferably an alkyl group having 1to 6 carbon atoms), an alkoxyl group (preferably an alkoxyl group having1 to 6 carbon atoms), an alkoxycarbonyl group (preferably analkoxycarbonyl group wherein the alkoxyl moiety has 1 to 6 carbonatoms), an acyl group (preferably an alkanoyl group having 2 to 6 carbonatoms), a halogen atom, a cyano group, a nitro group and the like.

[0034] The α,β-unsaturated carboxylic acid (I-1) is encompassed inα,β-unsaturated carboxylic acid (I), and the furan derivative (II-1) isencompassed in furan derivative (II). The7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (III-1) isencompassed in 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acidderivative (III), and 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acidderivative (IV-1) is encompassed in7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV).

[0035] The reaction of α,β-unsaturated carboxylic acid (I) with furanderivative (II) can be carried out in the presence or absence of asolvent. The solvent to be used is free of any particular limitation aslong as it does not adversely affect the reaction. Examples of thesolvent include an aliphatic hydrocarbon such as pentane, hexane,heptane, octane and petroleum ether; an aromatic hydrocarbon such asbenzene, toluene, xylene, ethylbenzene and cumene; an ether such asdiethyl ether, tetrahydrofuran, diisopropyl ether, dimethoxyethane,dibutyl ether and 1,4-dioxane; a halogenated hydrocarbon such asdichloromethane, chloroform, carbon tetrachloride, dichloroethane,trichloroethane, chlorobenzene and dichlorobenzene; or a mixed solventthereof; and the like. The amount of the solvent to be used is free ofany particular limitation, but it is generally preferably a 0.1 to100-fold weight relative to α,β-unsaturated carboxylic acid (I).

[0036] Examples of the Lewis acid include anhydrous aluminum chloride,aluminum bromide, diethylaluminum chloride, gallium chloride, galliumbromide, gallium iodide, anhydrous ferric chloride, anhydrous ferricbromide, zinc chloride, zinc bromide, zinc iodide, titanium chloride,titanium iodide, anhydrous stannous chloride, stannous bromide,anhydrous stannic chloride, a borane-tetrahydrofuran complex (BH₃.THF),a borane-dimethyl sulfide complex (BH₃.(CH₃)₂S), boron trichloride,boron tribromide, a boron trifluoride-diethyl ether complex(BF₃.(C₂H₅)₂O), a chloroborane-diethyl ether complex (BH₂Cl.(C₂H₅)₂O), achloroborane-dimethyl sulfide complex (BH₂Cl.(CH₃)₂S), adichloroborane-dimethyl sulfide complex (BHCl₂.(CH₃)₂S), abromoborane-dimethyl sulfide complex (BH₂Br.(CH₃)₂S), adibromoborane-dimethyl sulfide complex (BHBr₂.(CH₃)₂S); an acyloxyboranecompound such as tris(2,4,6-trimethylbenzoyloxy)borane,bis(chloroacetoxy)borane, triacetoxyborane, tri(fluoroacetoxy)borane,tripropionyloxyborane, triacryloyloxyborane, trimethacryloyloxyborane; adioxoborane compound such asa-[2,6-bis(isopropoxy)benzoyl]oxy-5-oxo-1,3,2-dioxaborane; anoxazaborolidine compound such as4-isopropyl-3-paratoluenesulfonyl-1,3,2-oxazaborolidin-5-one and4-t-butyl-3-paratoluenesulfonyl-1,3,2-oxazaborolidin-5-one; and thelike. Of these, anhydrous aluminum chloride, anhydrous ferric chloride,zinc chloride, a borane-tetrahydrofuran complex, a borane-dimethylsulfide complex, boron trichloride, boron tribromide, a borontrifluoride-diethyl ether complex, a chloroborane-diethyl ether complex,a chloroborane-dimethyl sulfide complex, a dichloroborane-dimethylsulfide complex, a bromoborane-dimethyl sulfide complex, adibromoborane-dimethyl sulfide complex and a boron compound such as theabove-mentioned acyloxyborane compound, the above-mentioned dioxoboranecompound or the above-mentioned oxazaborolidine compound is preferablyused, and a boron compound is particularly preferably used in view ofeasiness of work-up and high selectivity of the obtained objectivecompound. The boron compound to be used in the present invention hasLewis acidity and the Lewis acidity refers to the property capable ofaccepting an unshared electron pair. The amount of the Lewis acid to beused is preferably 0.001 to 1 equivalent, more preferably 0.005 to 0.2equivalent, relative to α,β-unsaturated carboxylic acid (I).

[0037] The amount of furan derivative (II) to be used is free of anyparticular limitation, but it is preferably 0.1 mole to 30 moles, morepreferably 1 mole to 20 moles, per 1 mole of α,β-unsaturated carboxylicacid (I). In addition, the reaction temperature is preferably −80° C. to80° C., more preferably −20° C. to 30° C. To preferentially obtain theendo form of a 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acidderivative, the reaction temperature is particularly preferably −10° C.to 5° C.

[0038] The reaction is preferably carried out by, for example, mixingα,β-unsaturated carboxylic acid (I), furan derivative (II) and, wherenecessary, a solvent, and then a Lewis acid to the resulting mixedsolution, or mixing furan derivative (II), a Lewis acid and, wherenecessary, a solvent, and then α,β-unsaturated carboxylic acid (I) tothe resulting mixed solution.

[0039] The 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative(III) or 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative (IV)thus obtained can be purified and separated according to a methodgenerally employed for the purification and separation of organiccompounds. For example, the reaction mixture is poured into water,extracted with an organic solvent such as pentane, hexane, petroleumether, benzene, toluene, diethyl ether, diisopropyl ether, ethylacetate, dichloromethane, chloroform and the like, and the extract isdried over anhydrous sodium sulfate and the like and concentrated. Theobtained crude product is purified as necessary by recrystallization,distillation, chromatography and the like. Depending on the reactionconditions, a product is precipitated in the reaction mixture with theprogress of the reaction, and the reaction mixture after the reactionmay be filtered off as it is, or the reaction mixture may be cooled toallow precipitation of the product, and the resulting crystals may beisolated by filtration.

EXAMPLE

[0040] The present invention is described in more detail by means of thefollowing Examples, which are not to be construed as limitative.

Example 1

[0041] The inside of a three-neck flask (inside volume 2000 ml) equippedwith a thermometer and a mechanical stirrer was substituted withnitrogen, and distilled furan (816 g, 12 mol) and acrylic acid (288 g,4.0 mol) were charged therein. The mixture was cooled to an innertemperature of 2° C. To this mixed solution was added dropwise asolution (43 ml, 0.04 mol) of a borane-tetrahydrofuran complex (BH₃.THF)in 0.93 M tetrahydrofuran over 20 min., while maintaining the innertemperature at not more than 2° C. After the completion of the dropwiseaddition, the mixture was stirred at the same temperature for 18 hr. Theresulting crystals were collected by filtration through a glass filter,washed with hexane (300 ml) cooled to not more than 5° C. and driedunder reduced pressure for 2 hr. to giveendo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorlesscrystals (352 g, purity >99%, yield 63% based on acrylic acid), thatshowed the following properties.

[0042] endo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid

[0043] melting point: 90.0-91.0° C.

[0044]¹H-NMR spectrum (270 MHz, CDCl₃, TMS, ppm) δ: 1.55 (dd, 1H, J=10Hz, 4 Hz), 2.13 (m, 1H), 3.17 (m, 1H), 5.06 (d, 1H, J=4 Hz), 5.23 (d,1H, J=4 Hz), 6.28 (dd, 1H, J=6 Hz, 4 Hz), 6.45 (dd, 1H, J=6 Hz, 2 Hz)

[0045] Methanol (5 ml) was added to the mother liquor after filtrationof the produced crystals and the mixture was concentrated to give7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid (199 g, endo form:exoform=45:55, purity 90%, yield 32% based on acrylic acid). The ¹H-NMRspectrum of the exo form were as follows.

[0046] exo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid

[0047]¹H-NMR spectrum (270 MHz, CDCl₃, TMS, ppm) δ: 1.57 (dd, 1H, J=12Hz, 8 Hz), 2.15 (m, 1H), 2.45 (dd, 1H, J=8 Hz, 4 Hz), 5.10 (d, 1H, J=4Hz), 5.23 (s, 1H), 6.35 (m, 2H)

Example 2

[0048] The inside of a three-neck flask (inside volume 500 ml) equippedwith a thermometer and a mechanical stirrer was substituted withnitrogen, and distilled furan (204 g, 3.0 mol) and acrylic acid (72 g,1.0 mol) were charged therein. The mixture was cooled to an innertemperature of 2° C. To this mixed solution was added dropwise aborane-dimethyl sulfide complex (BH₃.Me₂S) (0.95 ml, 0.01 mol) over 2min., while maintaining the inner temperature at not more than 2° C.After the completion of the dropwise addition, the mixture was stirredat the same temperature for 18 hr. The resulting crystals were collectedby filtration through a glass filter, washed with hexane (100 ml) cooledto not more than 5° C. and dried under reduced pressure for 2 hr. togive 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorlesscrystals (81 g, endo form:exo form=92:8, purity >99%, yield 58% based onacrylic acid).

Example 3

[0049] The inside of a three-neck flask (inside volume 500 ml) equippedwith a thermometer and a mechanical stirrer was substituted withnitrogen, and distilled furan (136 g, 2.0 mol), acrylic acid (72 g, 1.0mol) and diisopropyl ether (70 ml) as a solvent were charged therein.The mixture was cooled to an inner temperature of 2° C. To this mixedsolution was added dropwise a solution (11 ml, 0.01 mol) of aborane-tetrahydrofuran complex (BH₃.THF) in 0.93 M tetrahydrofuran over10 min., while maintaining the inner temperature at not more than 2° C.After the completion of the dropwise addition, the mixture was stirredat the same temperature for 4 hr. The resulting crystals were collectedby filtration through a glass filter, washed with diisopropyl ether (100ml) cooled to not more than 5° C. and dried under reduced pressure for 2hr. to give 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorlesscrystals (81 g, endo form:exo form=95:5, purity >99%, yield 58% based onacrylic acid).

Example 4

[0050] The inside of a three-neck flask (inside volume 100 ml) equippedwith a thermometer and a mechanical stirrer was substituted withnitrogen, and distilled furan (41 g, 600 mmol) and acrylic acid (7.2 g,100 mmol) were charged therein. The mixture was cooled to an innertemperature of 2° C. To this mixed solution was added dropwise a borontrifluoride-diethyl ether complex (BF₃.(C₂H₅)₂O) (0.1 ml, 1.0 mmol) over1 min., while maintaining the inner temperature at not more than 2° C.After the completion of the dropwise addition, the mixture was stirredat the same temperature for 5 hr. Water (10 ml) was added to thereaction mixture and the organic layer and the aqueous layer wereseparated. The aqueous layer was extracted twice with dichloromethane(10 ml) and the extract was combined with the organic layer separatedearlier. The mixture was dried over anhydrous sodium sulfate,concentrated and dried under reduced pressure for 2 hr. to give7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorless crystals(6.0 g, endo form:exo form=69:31, purity 96% (containing 4% of unreactedacrylic acid), yield 41% based on acrylic acid).

Example 5

[0051] Distilled furan (20.4 g, 300 mmol) and acrylic acid (7.2 g, 100.0mmol) were charged in a similar reactor as in Example 4, and the mixturewas cooled to an inner temperature of 2° C. To this mixed solution wasadded dropwise a solution (1.1 ml, 1.0 mmol) of a borane-tetrahydrofurancomplex (BH₃.THF) in 0.93 M tetrahydrofuran over 5 min., whilemaintaining the inner temperature at not more than 2° C. After thecompletion of the dropwise addition, the mixture was stirred at the sametemperature for 25 hr. Water (10 ml) and chloroform (10 ml) were addedto the reaction mixture and the organic layer and the aqueous layer wereseparated. The aqueous layer was extracted twice with chloroform (10 ml)and the extract was combined with the organic layer separated earlier.The mixture was dried over anhydrous sodium sulfate, concentrated anddried under reduced pressure for 2 hr. to give7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as pale yellow crystals(12.6 g, endo form:exo form=77:23, purity 97% (containing 3% ofunreacted acrylic acid), yield 87% based on acrylic acid).

Example 6

[0052] 3-Methylfuran (15.4 g, 187 mmol) and acrylic acid (7.2 g, 100mmol) were charged in a similar reactor as in Example 4, and the mixturewas cooled to an inner temperature of 2° C. To this mixed solution wasadded dropwise a solution (1.1 ml, 1.0 mmol) of a borane-tetrahydrofurancomplex (BH₃.THF) in 0.93 M tetrahydrofuran over 5 min., whilemaintaining the inner temperature at not more than 2° C. After thecompletion of the dropwise addition, the mixture was stirred at the sametemperature for 24 hr. The resulting crystals were collected byfiltration through a glass filter, washed with hexane (10 ml) cooled tonot more than 5° C. and dried under reduced pressure for 2 hr. to giveendo-6-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid ascolorless crystals (1.9 g, purity >99%, yield 9.5% based on acrylicacid), which showed the following properties.

[0053] endo-6-methyl-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic Acid

[0054] melting point: 129.5 to 130.0° C.

[0055]¹H-NMR spectrum (270 MHz, CDCl₃, TMS, ppm) δ: 1.56 (dd, 1H, J=12Hz, 4 Hz), 1.86 (d, 3H, J=2 Hz), 2.08 (m, 1H), 3.18 (m, 1H), 4.76 (d,1H, J=5 Hz), 5.10 (d, 1H, J=4 Hz), 5.82 (d, 1H, J=2 Hz)

Example 7

[0056] The inside of a three-neck flask (inside volume 25 ml) equippedwith a thermometer and a magnetic stirrer was substituted with nitrogen,and distilled furan (4.1 g, 60 mmol) and acrylic acid (3.6 g, 50.0 mmol)were charged therein. Then, zinc chloride (0.68 g, 5.0 mmol) was addedand the mixture was stirred at 20° C. for 21 hr. Water (10 ml) andchloroform (10 ml) were added to the reaction mixture and the organiclayer and the aqueous layer were separated. The aqueous layer wasextracted twice with chloroform (10 ml) and the extract was combinedwith the organic layer separated earlier. The mixture was dried overanhydrous sodium sulfate, concentrated and dried under reduced pressurefor 2 hr. to give 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid aspale yellow crystals (3.8 g, endo form:exo form=64:36, purity 95%(containing 5% of unreacted acrylic acid), yield 51% based on acrylicacid).

Example 8

[0057] Distilled furan (17.0 g, 250 mmol) and maleic acid (5.8 g, 50.0mmol) were charged in a similar reactor as in Example 4, and the mixturewas cooled to an inner temperature of 2° C. To this mixed solution wasadded dropwise a solution (5.4 ml, 5.0 mmol) of a borane-tetrahydrofurancomplex (BH₃.THF) in 0.93 M tetrahydrofuran over 20 min., whilemaintaining the inner temperature at not more than 2° C. After thecompletion of the dropwise addition, the mixture was stirred at the sametemperature for 5 hr. The resulting crystals were collected byfiltration through a glass filter, washed with hexane (30 ml) cooled tonot more than 5° C. and dried under reduced pressure for 2 hr. to giveendo,endo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic acid ascolorless crystals (4.1 g, purity >99%, yield 45% based on maleic acid),which showed the following properties.

[0058] endo,endo-7-oxabicyclo[2.2.1]hept-5-ene-2,3-dicarboxylic Acid

[0059] melting point: 148.0 to 149.0° C.

[0060]¹H-NMR spectrum (270 MHz, DMSO-d₆, TMS, ppm) δ: 3.25 (s, 2H), 5.01(s, 2H), 6.24 (s, 2H)

Example 9

[0061] Distilled furan (6.8 g, 100 mmol) and 2-bromoacrylic acid (1.0 g,6.6 mmol) were charged in a similar reactor as in Example 7, and themixture was cooled to an inner temperature of 2° C. To this mixedsolution was added dropwise a solution (0.7 ml, 0.7 mmol) of aborane-tetrahydrofuran complex (BH₃.THF) in 0.93 M tetrahydrofuran over5 min., while maintaining the inner temperature at not more than 2° C.After the completion of the dropwise addition, the mixture was stirredat the same temperature for 10 hr. Water (10 ml) and chloroform (10 ml)were added to the reaction mixture and the organic layer and the aqueouslayer were separated. The aqueous layer was extracted twice withchloroform (10 ml) and the extract was combined with the organic layerseparated earlier. The mixture was dried over anhydrous sodium sulfate,concentrated and dried under reduced pressure for 2 hr. to give2-bromo-7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as a pale-yellowoily substance (1.3 g, main component:minor component=2:1, purity 77%(containing 23% of unreacted 2-bromoacrylic acid), yield 70% based on2-bromoacrylic acid) being a mixture of an endo form and an exo form.

[0062] Main Component

[0063]¹H-NMR spectrum (270 MHz, CDCl₃, TMS, ppm) δ: 1.74 (d, 1H, J=13Hz), 2.94 (dd, 1H, J=13 Hz, 5 Hz), 5.10 (dd, 1H, J=5 Hz, 2 Hz), 5.47 (s,1H), 6.40 (dd, 1H, J=7 Hz, 2 Hz), 6.59 (d, 1H, J=7 Hz)

[0064] Minor Component

[0065]¹H-NMR spectrum (270 MHz, CDCl₃, TMS, ppm) δ: 2.41 (d, 1H, J=13Hz), 2.57 (dd, 1H, J=13 Hz, 5 Hz), 5.15 (dd, 1H, J=5 Hz, 2 Hz), 5.21 (s,1H), 6.50 (dd, 1H, J=7 Hz, 2 Hz), 6.59 (d, 1H, J=7 Hz)

Example 10

[0066] Distilled furan (9.4 g, 138 mmol) and acrylic acid (1.8 g, 25.0mmol) were charged in a similar reactor as in Example 7, and thenanhydrous ferric chloride (0.41 g, 2.5 mmol) was added. The mixture wasstirred under a nitrogen atmosphere at an inner temperature of 5° C. for5 hr. Water (10 ml) and chloroform (10 ml) were added to the reactionmixture and the organic layer and the aqueous layer were separated. Theaqueous layer was extracted twice with chloroform (10 ml) and theextract was combined with the organic layer separated earlier. Themixture was dried over anhydrous sodium sulfate, concentrated and driedunder reduced pressure for 2 hr. to give7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as pale-yellow crystals(3.1 g, endo form:exo form=64:36, purity 94% (containing 6% of unreactedacrylic acid), yield 83% based on acrylic acid).

Example 11

[0067] Distilled furan (9.4 g, 138 mmol) and acrylic acid (1.8 g, 25.0mmol) were charged in a similar reactor as in Example 7, and thenanhydrous aluminum chloride (0.33 g, 2.5 mmol) was added. The mixturewas stirred under a nitrogen atmosphere at an inner temperature of 5° C.for 5 hr. Water (10 ml) and chloroform (10 ml) were added to thereaction mixture and the organic layer and the aqueous layer wereseparated. The aqueous layer was extracted twice with chloroform (10 ml)and the extract was combined with the organic layer separated earlier.The mixture was dried over anhydrous sodium sulfate, concentrated anddried under reduced pressure for 2 hr. to give7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as pale-yellow crystals(3.0 g, endo form:exo form=67:33, purity 93% (containing 7% of unreactedacrylic acid), yield 80% based on acrylic acid).

Example 12

[0068] Distilled furan (141.7 g, 2.08 mol) and triacetoxyborane (1.19 g,6.63 mmol) were charged in a similar reactor as in Example 4, and themixture was cooled to −5° C. To this mixed solution was added acrylicacid (30.4 g, 0.42 mol) and the mixture was stirred at an innertemperature of −5° C. for 22 hr. The resulting crystals were collectedby filtration through a glass filter, washed with diisopropyl ether (60ml) cooled to not more than 5° C. and dried under reduced pressure for 2hr. to give 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorlesscrystals (11.4 g, endo form:exo form=98:2, purity >99%, yield 43% basedon acrylic acid).

Example 13

[0069] Distilled furan (141.7 g, 2.08 mol) and tripropionyloxyborane(1.55 g, 6.75 mmol) were charged in a similar reactor as in Example 4,and the mixture was cooled to −5° C. To this mixed solution was addedacrylic acid (30.1 g, 0.42 mol) and the mixture was stirred at an innertemperature of −5° C. for 15 hr. The resulting crystals were collectedby filtration through a glass filter, washed with diisopropyl ether (60ml) cooled to not more than 5° C. and dried under reduced pressure for 2hr. to give 7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid as colorlesscrystals (22.5 g, endo form:exo form=99:1, purity >99%, yield 39% basedon acrylic acid).

INDUSTRIAL APPLICABILITY

[0070] According to the present invention,7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives,particularly an endo form thereof, can be industrially advantageouslyproduced directly from α,β-unsaturated carboxylic acid (I) and furanderivative (II) under mild conditions in a high yield. The method of thepresent invention can advantageously produce7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivatives,particularly an endo form thereof, under mild conditions (i.e., withoutheating at a high temperature or pressurization) in a shorter reactiontime in a high yield, as compared to conventional methods, and issuitable for industrial production.

[0071] This application is based on a patent application No. 2000-282140filed in Japan, the contents of which are hereby incorporated byreference.

What is claimed is:
 1. A production method of a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of theformula (III)

wherein R¹ R² and R³ are each independently a hydrogen atom, a halogenatom, a formyl group, a cyano group, a carboxyl group, an alkoxycarbonylgroup, an acyl group, an acyloxy group, an organic sulfinyl group, anorganic sulfonyl group or an alkyl group optionally having substituents,or R¹ and R² may form a ring together with the carbon atoms they arebonded to; and R⁴, R⁵, R⁶ and R⁷ are independently a hydrogen atom, analkoxyl group, an alkylthio group or an alkyl group optionally havingsubstituents, or R⁴ and R⁵, and R⁵ and R⁶ may form a ring together withthe carbon atoms they are bonded to, or the formula (IV)

wherein R¹, R², R³, R⁴, R⁵, R⁶ and R⁷ are as defined above, whichcomprises: reacting an α,β-unsaturated carboxylic acid of the formula(I)

wherein R¹, R² and R³ are as defined above, with a furan derivative ofthe formula (II)

wherein R⁴, R⁵, R⁶ and R⁷ are as defined above, in the presence of aLewis acid.
 2. A production method of a7-oxabicyclo[2.2.1]hept-5-ene-2-carboxylic acid derivative of theformula (III-1)

wherein R¹¹, R²¹ and R³¹ are each independently a hydrogen atom, ahalogen atom or a carboxyl group, or R¹¹ and R²¹ may form a ringtogether with the carbon atoms they are bonded to, and R⁴¹, R⁵¹, R⁶¹ andR⁷¹ are each independently a hydrogen atom or an alkyl group optionallyhaving substituents, or R⁴¹ and R⁵¹, and R⁵¹ and R⁶¹ may form a ringtogether with the carbon atoms they are bonded to, or the formula (IV-1)

wherein R¹¹, R²¹ R³¹, R⁴¹, R⁵¹, R⁶¹ and R⁷¹ are as defined above, whichcomprises: reacting an α,β-unsaturated carboxylic acid of the formula(I-1)

wherein R¹¹, R²¹ and R³¹ are as defined above, with a furan derivativeof the formula (II-1)

wherein R⁴¹, R⁵¹, R⁶¹ and R⁷¹ are as defined above, in the presence of aLewis acid.
 3. The production method of claim 1 or 2, wherein a boroncompound having Lewis acidity is used as the Lewis acid.
 4. Theproduction method of claim 1 or 2, wherein the Lewis acid is selectedfrom the group consisting of a borane-tetrahydrofuran complex, aborane-dimethyl sulfide complex, a boron trifluoride-diethyl ethercomplex, triacetoxyborane and tripropionyloxyborane.